A novel phenotype-based approach for systematically screening antiproliferation metallodrugs

Ruthenium (Ru) derivatives have less toxicity and higher water-solubility than cisplatin, giving them great potential as antitumor metallodrugs. In this study, zebrafish were employed as a whole-organism model to screen new Ru compounds for anti-cell proliferation activity. After soaking fish embryos in cisplatin and five Ru derivatives, [Ru(terpy)(bpy)Cl]Cl, [Ru(terpy)(dPPZ)OH2](ClO4)(2). [Ru(terpy)(tMen)OH2](ClO4)(2), [Ru(terpy)(Me(4)Phen)OH2](ClO4)(2), and Ru(bpy)(2)Cl-2, only cisplatin and [Ru(terpy)(bpy)Cl]Cl-treated ernbryos displayed obvious phenotypic effects. such as fin-reduction. After further modification of [Ru(terpy)(bpy)Cl]Cl's main structure and the synthesis of two structurally related compounds, [Ru(terpy)(dcbpyH(2))Cl]Cl and [Ru(terpy)(dmbpy)Cl]Cl, only [Ru(terpy)(dmbpy)Cl]Cl exhibited fin-reduction phenotypes. TUNEL assays combined with immunostaining techniques revealed that treatment with cisplatin, [Ru(terpy)(bpy)Cl]Cl, and [Ru(terpy)(dmbpy)Cl]Cl led proliferating fin mesenchymal cells to undergo apoptosis and consequently caused fin-reduction phenotypes. Furthermore. [Ru(terpy)(bpy)Cl]Cl was able to activate the P53-dependent and independent pathways. and induced human hepatoma cells to undergo apoptosis. In summary. it was concluded that the zebrafish model was effective for the screening of phenotype-based antiproliferation metallodrugs. (C) 2009 Elsevier Ireland Ltd. All rights reserved.